Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH2:64])[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1.[CH3:65][C:66]1[C:78]([CH3:79])=[CH:77][C:69]2[N:70]([CH2:73][C:74](O)=[O:75])[CH:71]=[N:72][C:68]=2[CH:67]=1>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH:64][C:74](=[O:75])[CH2:73][N:70]2[C:69]3[CH:77]=[C:78]([CH3:79])[C:66]([CH3:65])=[CH:67][C:68]=3[N:72]=[CH:71]2)[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1
Reactant: NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1
Reactant: Cc1cc2ncn(CC(=O)O)c2cc1C
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Product: Cc1cc2ncn(CC(=O)NC(Cc3cc(F)cc(F)c3)c3ncoc3-c3ccc(Cl)cc3)c2cc1C

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 33G and 2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid. 1H NMR (400 MHz, dmso) δ 9.36 (d, J=8.3 Hz, 1H), 9.11 (s, 1H), 8.55 (s, 1H), 7.63-7.53 (m, 3H), 7.45 (d, J=8.3 Hz, 2H), 7.20 (s, 1H), 6.98 (d, J=8.7 Hz, 1H), 6.88 (d, J=7.2 Hz, 2H), 5.36 (d, J=7.5 Hz, 1H), 5.17-5.01 (m, 2H), 3.27-3.10 (m, 2H), 2.35 (s, 3H), 2.29 (s, 3H). MS (m/z) 521.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:21][CH:22]([CH3:26])[CH:23](O)[CH3:24].C(#N)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)[CH:23]([CH:22]([CH3:26])[CH3:21])[CH3:24])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)C(C)O
Reactant: CC(C)c1ccc(NS(=O)(=O)c2ccc(F)cc2)nc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)c1ccc(N(C(C)C(C)C)S(=O)(=O)c2ccc(F)cc2)nc1
Temperature: 150 °C
Yield: 12.7 %

Procedure:
To a solution of 4-fluoro-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (203 mg, 0.690 mmol) and 3-methylbutan-2-ol (60.8 mg, 0.690 mmol) in toluene (3 mL) stirred in air at room temperature was added a solution of 2-tributylphosphoranylidene)acetonitrile (166 mg, 0.690 mmol) in toluene (0.5 mL). The reaction vessel was sealed and heated by microwaves to 150° C. for 30 minutes. After cooling, the solvent was evaporated in vacuo and the crude purified by mass directed autoprep (formic acid modifier) to give the title product (32 mg) as a colourless oil. LCMS (2 min, formic) Rt 1.41 min, m/z (ES+) 365 (M+H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:6]([F:18])[CH:5]=1.[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([CH2:34][C:35](O)=[O:36])[N:27]=[C:28]([C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)[C:21]=12.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([CH2:34][C:35]([N:15]3[CH2:14][CH2:13][N:12]([C:7]4[CH:8]=[C:9]([O:10][CH3:11])[C:4]([Cl:3])=[CH:5][C:6]=4[F:18])[CH2:17][CH2:16]3)=[O:36])[N:27]=[C:28]([C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)[C:21]=12
Reactant: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)O
Reactant: COc1cc(N2CCNCC2)c(F)cc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4c(N)ncnc43)CC2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-chloro-2-fluoro-5-methoxyphenyl)-piperazine dihydrochloride salt (65.2 mg, 0.206 mmol, 1 equiv), [4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]acetic acid (50 mg, 1 equiv), BOP reagent (109 mg, 1.7 equiv) and N,N-diisopropylethylamine (0.165 mL, 5 equiv) in DMF (0.5 mL) was stirred at room temperature overnight. Reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) purification gave 2-[4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)-piperazin-1-yl]ethanone. MS (ES) m/z 486.5 (M+H+).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[CH3:13][N:14]([CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23])[CH3:15].[Cl-:30].[NH4+]>CCOCC>[ClH:30].[CH3:15][N:14]([CH:16]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1)[OH:23])[CH3:13]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: [Cl-]
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)c1ccc(C(F)(F)F)cc1
Product: Cl
Temperature: 25 °C
Yield: 61.7 %

Procedure:
0.76 g (31.0 mmole) of magnesium turnings was stirred in 15 ml. of ether of analysis purity. 4.46 ml (31.0 mmole) of 4-bromobenzotrifluoride dissolved in 15 ml of ether were arddecl dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 6.0 g (26.0 mmole) of the 2-{dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 50 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 8.49 g of crude base (86.7% of threory) were obtained, from which 6.62 g of 2-{dimethylaminophenylmethyl)-1-(4-trifluoromethylphenyl)cyclohexanol, hydrochloride (61.7% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 170° C.
Reaction SMILES: C1C=CC=CC=1.[C:7](Cl)(Cl)=[O:8].[C:11]1([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-:25][C:26]#[N:27].[K+]>CN(C=O)C>[C:11]1([N:17]2[C:18](=[O:19])[N:20]([CH2:21][CH2:22][CH2:23][CH3:24])[C:26](=[O:25])[NH:27][C:7]2=[O:8])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCCNC(=O)Nc1ccccc1
Reactant: O=C(Cl)Cl
Reactant: N#C[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCn1c(=O)[nH]c(=O)n(-c2ccccc2)c1=O
Yield: 70 %

Procedure:
A benzene solution (50 ml) of 5-phenyl-3-butyl allophanoyl chloride (0.1 mole) was prepared by reaction of phosgene with 1-phenyl-3-butyl urea by the method of Example 2. This solution was added dropwise to 16.0 g of potassium cyanate in 300 ml of anhydrous DMF as described in Example 3. After similar work-up, 17.0 g (70% yield) of 3-phenyl-5-butyl isocyanuric acid was obtained; b.p. 172° C./.01 mm, m.p. 54°-56° C. IR and NMR analysis were consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][N:14]=1)(=[O:12])=[O:11].Br[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25]>>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([S:10]([N:9]([CH2:23][C:24]([OH:26])=[O:25])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:12])=[O:11])=[N:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(C(C)C)cn1
Product: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of 5-isopropyl-pyridine-2-sulfonic acid (2-methoxy-phenyl)-amide with tert-butyl bromoacetate
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[O:15]=[C:16]1[CH2:19][O:18][CH2:17]1.[Cl-].[NH4+]>C(OCC)C.C1COCC1.O>[OH:15][C:16]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:19][O:18][CH2:17]1
Reactant: N#Cc1ccc(I)cc1
Reactant: O=C1COC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(O)COC2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Under inert conditions, 11 ml (21.8 mmol) of a 2 M solution of isopropylmagnesium chloride in diethyl ether were added dropwise at −40° C. to a solution of 5.0 g (21.8 mmol) of 4-iodobenzonitrile in 100 ml of anhydrous THF. After the mixture had been stirred at the same temperature for 1.5 h, it was cooled down to −78° C. and, with the aid of a cannula, was slowly added to a solution, likewise cooled to −78° C., of 2.95 g (32.7 mmol, 80% in dichloromethane) of 3-oxooxetane [G. Wuitschik et al., Angew. Chem. Int. Ed. Engl. 2006, 45 (46), 7736-7739] in 100 ml of anhydrous THF. After the addition had ended, the reaction mixture was stirred first at −78° C. for 10 min, then at 0° C. for 2 h and finally at RT for 30 min. Then a few ml of saturated aqueous ammonium chloride solution were added. Subsequently, the solvent was substantially removed on a rotary evaporator. The residue obtained was diluted with 200 ml of water and extracted three times with approx. 200 ml each time of ethyl acetate. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the solvent was removed on a rotary evaporator. The resulting crude product was purified by crystallization from 10:1 cyclohexane/ethyl acetate. 2.42 g (63% of theory) of the title compound were obtained.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.Cl.NC1C=CC(C(O)=O)=CC=1>O1CCCC1>[C:1]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(C(=O)O)cc1
Yield: 78.8 %

Procedure:
0.66 g (7.3 mmoles) of acryloyl chloride was added to a solution of 2 g (14.3 mmoles) of p-aminobenzoic acid in 40 mL tetrahydrofuran (THF). A white precipitate consisting of p-aminobenzoic acid hydrochloride formed. The suspension was filtered and the filtrate was dried by vacuum evaporation to yield 1.1 g p-acrylamidobenzoic acid (reaction shown in FIG. 16a).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH2:15]3)=[N:11][C:10]=2[C:30]([OH:32])=O)=[CH:5][CH:4]=1.[CH2:35]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[CH2:45][NH2:46])[CH:36]([CH3:38])[CH3:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:35]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[CH2:45][NH:46][C:30]([C:10]1[N:11]=[C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[C:25]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:18][CH2:19]2)[NH:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:33])[F:34])=[CH:4][CH:5]=1)=[O:32])[CH:36]([CH3:38])[CH3:37]
Reactant: O=C(O)c1nc(N2CCN(c3ncccc3C(F)(F)F)CC2)[nH]c1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)CN1CCCCC1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN1CCCCC1CNC(=O)c1nc(N2CCN(c3ncccc3C(F)(F)F)CC2)[nH]c1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1H-imidazole-4-carboxylic acid from step (d) above (50. mg, 0.103 mmol), (1-isobutylpiperidin-2-yl)methanamine (26 mg, 0.15 mmol, Example 29(c)), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (68 mg, 0.154 mmol, Aldrich), and DIEA (0.053 mL, 0.975 mmol, Aldrich) in DCM (0.6 mL) reacted under the condition of Example 16(f) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 638 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([O:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:26](=[O:35])[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(N(C(C)C)CC)(C)C.[N:45]1([CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[O:35]=[C:26]1[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C@H:12]([CH2:11][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)[C:13](=[O:14])[N:54]3[CH2:55][CH2:56][CH:51]([N:45]4[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]4)[CH2:52][CH2:53]3)=[O:18])[CH2:20][CH2:21]2)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn[nH]c12
Reactant: C1CCN(C2CCNCC2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (500 mg, 1.05 mmol), diisopropylethylamine (0.37 mL, 2.11 mmol), and 4-piperidinopiperidine (355 mg, 2.0 equiv) in dimethylformamide (4 mL) and dichloromethane (4 mL) at 0° C. was added PyBOP® (576 mg, 1.11 mmol). The reaction was stirred at 0° C. for 4 h, was concentrated, and purified by column chromatography (95:5:1 to 93:7:1 dichloromethane/methanol/triethylamine). The resulting residue was dissolved in 5% methanol/dichloromethane and passed through a basic alumina column to give 600 mg (88%) as a white powder. Mass spec.: 625.56 (MH)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[S:9][C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].S(O)(O)(=O)=O.Cl[C:24]1[NH:25][CH2:26][CH2:27][N:28]=1>ClCCl>[CH:1]([O:4][C:5]1[S:9][C:8]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:24]3[NH:28][CH2:27][CH2:26][N:25]=3)=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Cc2ccc(N)cc2)s1
Reactant: ClC1=NCCN1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)Oc1ccc(Cc2ccc(NC3=NCCN3)cc2)s1
Temperature: 80 °C
Yield: 89.7 %

Procedure:
To a solution of 4-(5-isopropoxythien-2-ylmethyl)-phenylamine (131 mg, 0.53 mmol) in aceonitrile (8 ml) was added 2-chloro-2-imidazoline sulfate (121 mg, 0.59 mmol) at 20–25° C. under argon. The mixture was heated at 80° C. for 1.5 hours. The mixture was diluted with dichloromethane and washed with sodium hydroxide, water, dried (Na2SO4) and concentrated to dryness. Purification by preparative TLC, eluting with ethyl acetate/methyl alcohol/isopropylamine, gave 2-[4-(5-isopropoxythien-2-ylmethyl)phenyl]amino-imidazoline (150 mg, 90%) as a thick yellow oil; 1H NMR (300 Mhz, CDCl3 δ 7.13 (d, J=8.4 Hz, 2H) 6.93 (d, J=8.4 Hz, 2H), 6.37 (dt, J=3.7, 1.0 Hz, 1H), 6.02 (d, J=3.7 Hz, 1H), 4.28 (quintet, J=6.2 Hz, 1H), 3.93 (bs, 2H), 3.52 (5, 4H), 3.24–3.5 (broad, 2H), 1.32 (d, J=6.2 Hz, 6H). MS m/e (%):316 (M+1, 100%). 2-[4-(5-isopropoxythien-2-ylmethyl)phenyl]amino-imidazoline oxalate, m.p. 134.4–135° C.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[CH2:26]([O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH:36]N)[CH:31]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:31]=1)[CH3:27]
Reactant: CCOC(=O)c1ccnc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: CCOC(=O)c1ccnc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 2-hydrazino-isonicotinic acid ethyl ester (described in Anales Real Soc. Espan. Fis. Quire. (Madrid) Ser. B (1963), 59(3), 179-84) according to example 43 gave the desired product. MS: M=454.0 (M+H)+
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([C:20]2([CH2:25][CH:26]([CH2:30][CH2:31][O:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.C(O)C.O.[OH-].[Na+]>O1CCOCC1>[C:9]([C@@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([C:20]2([CH2:25][CH:26]([CH2:30][CH2:31][O:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH2:13][CH2:12]1)([OH:10])=[O:8]
Reactant: CCOCCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)CCCC1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: CCOCCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1)C(=O)O
Reaction time: 20 h
Yield: 88.2 %

Procedure:
3-{1-[(cis-4-Benzyloxycarbonyl-cyclohexyl)carbamoyl]cyclopentyl}-2-(2-ethoxyethyl)propanoic acid (225 mg, 0.476 mmole) was dissolved in 1,4-dioxan (20 ml), ethanol (4 ml) and water (6 ml) and was treated with 1N sodium hydroxide solution (2.4 ml, 2.4 mmole). After 20 hours at room temperature, the solution was evaporated to half volume, diluted with water (20 ml) and washed with diethyl ether. The aqueous layer was separated, acidified with 2N hydrochloric acid and extracted with ethyl acetate (3×20 ml). The ethyl acetate layer was separated, dried over magnesium sulphate and the solvent evaporated to give the title product as a colourless foam (161 mg, 88%). Found: C,61.89; H,8.29; N,3.62. C20H33NO6,0.2 H2O requires C,62.06; H,8.69; N,3.62%.
Reaction SMILES: ClC1C=C2[C:8](=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)[C:6]([C:20]([O:22][CH2:23][CH3:24])=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.C[NH:61]C1CCOC1>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:61])=[O:50])=[C:33]2[S:53]([N:7]([CH3:8])[CH:6]1[CH2:24][CH2:23][O:22][CH2:20]1)(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CNC1CCOC1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: CN(C1CCOC1)S(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with (±)-N-methyl-N-tetrahydrofuran-3-ylamine, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:24]([NH:28][CH2:29][C:30]1[CH:42]=[CH:41][C:33]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:32]([CH3:43])[CH:31]=1)[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH2:24]([N:28]([CH2:29][C:30]1[CH:42]=[CH:41][C:33]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:32]([CH3:43])[CH:31]=1)[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: Clc1ccc(-c2cncc(Br)n2)cc1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(Cl)cc2)n1
Temperature: 100 °C
Yield: 16.7 %

Procedure:
A mixture of 2-bromo-6-(4-chlorophenyl)pyrazine (0.27 g, 1 mmol), N,N-diisopropylethylamine (0.18 mL, 1 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.42 g, 1.5 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The reaction mixture was then allowed to come to room temperature and the residue dissolved in CH2Cl2 (50 mL), the organic extract was washed water (15 mL) and passed through a hydrophobic frit before concentrating in vacuo. Purification by Biotage™ chromatography (Si, 40 g) eluting 1:9–1:1.5 EtOAc:cyclohexane afforded the title compound as a pale yellow oil 78 mg.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1>C(OC(C)=O)(C)C.[Pd]>[OH:8][CH2:9][CH:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1
Reactant: O=S1(=O)CCC(COCc2ccccc2)N1
Agent: [Pd]
Solvent: CC(=O)OC(C)C
Product: O=S1(=O)CCC(CO)N1
Reaction time: 72 h
Yield: 64.8 %

Procedure:
Dioxide 7 (40 g, 0.17 mol) was placed in the glass liner within a 2 L Parr hydrogenator and dissolved in a mixture of IMS (150 ml) and iPrOAc (150 ml). A suspension of 5% palladium on carbon (Johnson Matthey type 392.18 g) in iPrOAc (50 mL) was added and the suspension stirred under a hydrogen atmosphere of 70 psi for 3 days. After this time an NMR IPC was carried out that showed approx 15% benzylated material still present. After a further 4 days the reaction was 94% complete and it was decided to stop the hydrogenolysis. The palladium catalyst was filtered under nitrogen on a bed of celite, which was subsequently washed with IMS (250 mL) and iPrOAc (250 mL). The filtrate and washings were concentrated to give the crude product as an oil (26.26 g). The oil was purified by flash column chromatography (silica gel, DCM/methanol (9:1)) yielding 16.65 g (67%) of the hydroxyl-dioxide 8 as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]([OH:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1.FC(F)(F)C(O)=O>CS(C)=O>[CH3:1][N:2]([CH3:21])[S:3]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([OH:31])[CH3:30])[CH:24]=3)[N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc(-c2ccnc(S(C)(=O)=O)n2)s1
Reactant: CC(O)c1cccc(N)c1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(O)c1cccc(Nc2nccc(-c3ccc(S(=O)(=O)N(C)C)s3)n2)c1
Temperature: 100 °C
Yield: 62.5 %

Procedure:
5-(2-Methanesulfonyl-pyrimidin-4-yl)-thiophene-2-sulfonic acid dimethylamide (19.8 mg, 0.057 mmol), 1-(3-aminophenyl)ethanol (11.7 mg, 0.085 mmol) and trifluoroacetic acid (6.5 uL, 0.085 mmol) were combined in DMSO (0.5 M) and the mixture was heated in a capped vial at 100° C. for 16 hours. The dark solution was diluted with DMSO and purified by preparative LC. 5-{2-[3-(1-Hydroxyethyl)-phenylamino]-pyrimidin-4-yl}-thiophene-2-sulfonic acid dimethylamide (14.4 mg, 62.6%) was obtained as a brown solid after lyophilization. 1H NMR (500 MHz, DMSO-d6) δ 1.35 (d, J=6 Hz, 3H), 2.70 (s, 6H), 4.70 (m, 1H), 5.12 (d, J=4 Hz, 1H), 6.97 (br d, J=7 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 7.46 (d, J=5.5 Hz, 1H), 7.49 (br d, J=6.5 Hz, 1H), 7.71 (d, J=4 Hz, 1H), 7.91 (br s, 1H), 8.12 (d, J=4 Hz, 1H), 8.58 (d, J=5.0 Hz, 1H), 9.75 (s, 1H). MS: m/z 405 (M+H+).